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Fiscal Year: FY 2006  Task Last Updated:  01/08/2007 
PI Name: Goldberg, Alfred L Ph.D. 
Project Title: The Activation of Protein Breakdown in Muscle Upon Unloading and Possible Countermeasures 
   
Division Name: Human Research 
Program/Discipline--
Element/Subdiscipline:
NSBRI Teams--Muscle Alterations and Atrophy Team 
 
Joint Agency Name:   TechPort:  No 
Human Research Program Elements: None
Human Research Program Risks: None
Human Research Program Gaps: None
Space Biology Element: None
Space Biology Cross-Element Discipline: None
Space Biology Special Category: None
PI Email: alfred_goldberg@hms.harvard.edu  Fax:  617-232-0173 
PI Organization Type: UNIVERSITY  Phone: 617-432-1855  
Organization Name: Harvard Medical School 
PI Address 1: 240 Longwood Avenue 
PI Address 2: Bldg. C-1, Rm. 415 
PI Web Page:  
City: Boston  State: MA 
Zip Code: 02115-5817  Congressional District: 
Comments:  
Project Type: GROUND  Solicitation:  2003 Biomedical Research & Countermeasures 03-OBPR-04 
Start Date: 03/01/2004  End Date:  02/28/2007 
No. of Post Docs: No. of PhD Degrees: 
No. of PhD Candidates: No. of Master' Degrees: 
No. of Master's Candidates: No. of Bachelor's Degrees: 
No. of Bachelor's Candidates: Monitoring Center:  NSBRI 
Contact Monitor:   Contact Phone:   
Contact Email:  
Flight Program:  
Flight Assignment:

 

Key Personnel Changes/Previous PI:  
COI Name (Institution):  
Grant/Contract No.: NCC 9-58-MA00404 
Performance Goal No.:  
Performance Goal Text:

 

Task Description: The rapid loss of muscle mass that occurs in astronauts in space due to muscle unloading and in patients with many systemic diseases results primarily from accelerated degradation of muscle proteins. This enhancement of protein breakdown is mainly due to activation of the Ub-proteasome pathway. Our major goal is to clarify the biochemical basis for the activation of this proteolytic pathway and thus to develop pharmacological agents that reduce this excessive degradation and retard muscle wasting.

Recently, we identified a set of genes ("atrogenes") whose expression increases or decreases coordinately when muscles atrophy. In order to achieve a fuller understanding of the atrophy process and to develop novel inhibitors of the atrophy process, we plan to further study this transcriptional program and its regulation, especially after disuse. Of particular importance was the recent finding that the two genes induced most dramatically in atrophying muscles are the muscle-specific ubiquitin ligases (E3s), atrogin-1 (MAFbx) and MuRF1. If either of these enzymes is knocked out, the extent of muscle wasting is reduced. These Ub-ligases thus are very attractive therapeutic targets.

To fully understand the initiation of the atrophy process, and to develop rational countermeasures, we are also studying the signal transduction systems that activate transcription of these genes in simple models of muscle atrophy in cultured myotubes. We recently found that the key factor in muscle hypertrophy, IGF-1, rapidly suppresses the expression of atrogin-1 and MuRF1 and prevents their induction by glucocorticoids. These effects of IGF-1 appear to be mediated by the PI3-kinase-AKT pathway, which probably inactivates one of the Forkhead transcription factors. Our primary goals will be to identify the precise steps in this kinase cascade and the key transcription steps through which disuse and glucocorticoids activate and IGF-1 inhibits expression of atrogin-1 and MuRF1.

These studies should identify novel therapeutic targets (e.g. key kinases) or Foxo-regulatory factors whose inhibition blocks atrogin-1 and MuRF1 induction. Using these enzymes and "reporter gene” constructs, we shall screen libraries of small molecules for agents that prevent induction of atrogin-1 and MuRF1. Inhibiting the expression of these key ligases represents an exciting new therapeutic approach to prevent muscle wasting in space personnel and in diverse disease states. In addition, we are continuing to test whether inhibitors of proteasomes, both proved ones and the inhibitor (Velcade) now used in cancer therapy by partially retarding overall proteolysis may be useful in retarding muscle wasting.

 

Rationale for HRP Directed Research:

 

Research Impact/Earth Benefits: If successful, this research may yield novel therapies to prevent or treat the marked wasting of muscle seen in various bed-ridden patients (i.e. the elderly) and ones with various systemic diseases (including cardiac failure, cancer, sepsis, renal failure, AIDS).

 

Task Progress: A) Transcriptional Changes in Rapidly Atrophying and Atrophied Muscles.

Muscle atrophy occurs upon unloading and systemically in fasting and many catabolic diseases. We have identified a common set of genes (“atrogenes”), whose expression is coordinately induced or suppressed in muscle during these various wasting states. To determine whether this transcriptional program also functions during atrophy resulting from inactivity and if atrogene expression correlates with the rate of weight loss, we analyzed changes in gastrocnemius mRNA following denervation or disuse induced by spinal isolation. After these procedures, the loss of muscle weight was initially rapid and then slowed. At 3 days, 78% of the atrogenes identified during catabolic states were induced or repressed, especially the key ubiquitin-ligases, atrogin-1 and MuRF1, but at 14 days when atrophy has slowed, the expression of 92% of the atrogenes returned to basal levels, including all atrogenes related to protein breakdown. Subsequently, expression of a few atrogenes remained high in the disused muscle, including mRNA for the transcription factor, Foxo1, which may be important in maintenance of the “atrophied” state. Thus, 1) the atrophy in systemic diseases and following disuse share similar transcriptional adaptations. 2) Atrophy induced by disuse proceeds through multiple phases: the rapidly “atrophying” phase (when atrogene expression is pronounced) and “atrophied” muscles. 3) Because expression of atrogin-1 and MuRF1 appear responsible for the rapid muscle weight loss, these mRNAs can serve as useful biomarkers for evaluating countermeasures.

B) The Exercise-Induced Coactivator PGC-1 Inhibits Muscle Atrophy by Blocking FoxO3.

Our studies indicated that in atrophy induced by unloading, fasting, and systemic diseases, the FoxO family of transcription factors plays a critical role in activating protein breakdown. When activated, FoxO3 itself triggers expression of atrogin-1 and MuRF1 and causes profound atrophy. Physical exercise also influences fiber-type composition as well as fiber size in muscle. Others have shown that increased activity stimulates production of the transcriptional coactivator PGC-1alpha, which promotes switching from glycolytic towards more oxidative fibers and production of mitochondria. To understand how exercise might retard atrophy, we investigated whether PGC-1alpha is also important in the regulation of muscle size. In atrophying rodent muscles, the atrophying fibers showed markedly reduced expression of PGC-1alpha. In transgenic mice overexpressing PGC-1alpha, denervation caused little or no loss of fiber diameter, and atrogin-1 and MuRF1 induction was blocked. Also, transfection of PGC-1alpha into adult muscle fibers reduced the capacity of FoxO3 to cause fiber atrophy. Thus, PGC-1alpha and FoxO3 are important opposing factors in determining muscle mass. The production of PGC-1alpha upon exercise seems to reduce the catabolic effects of FoxO3, while the fall of PGC-1alpha with inactivity and catabolic states contributes to the FoxO-dependent loss of muscle protein.

C) Inhibition of Muscle Atrophy by Administrating the Proteasome Inhibitor, Velcade.

Because we demonstrated a key role of the proteasome in catalyzing the loss of muscle protein during atrophy, we investigated the capacity of Velcade (PS341), the proteasome inhibitor now approved by the FDA for cancer treatment to retard muscle atrophy. Following a section of the sciatic nerve in mice, clear atrophy of the gastrocnemius was evident by seven days. Injection of Velcade every other day reduced the weight loss of the muscles by 40% without any obvious toxicity. Studies are in progress to optimize the effective dose and to learn whether the inhibitor affects other forms of atrophy and whether these muscles also have greater functional capacity than those in untreated animals.

 

Bibliography Type: Description: (Last Updated: 09/01/2017) Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Goldberg AL, Sandri M, Sacheck J, Lecker S. "Molecular Mechanisms for the Loss of Muscle Protein in Catabolic States." 3rd Cachexia Conference (Rome, Italy), Dec 8-10, 2005.

Cachexia Conference (Rome, Italy). 2005. , Dec-2005

Articles in Peer-reviewed Journals Kisselev AF, Goldberg AL. "Monitoring activity and inhibition of 26S proteasomes with fluorogenic peptide substrates." Methods Enzymol. 2005;398:364-78. PMID: 16275343 , Sep-2005
Articles in Peer-reviewed Journals Lecker SH, Goldberg AL, Mitch WE. "Protein degradation by the ubiquitin-proteasome pathway in normal and disease states." J Am Soc Nephrol. 2006 Jul;17(7):1807-19. Epub 2006 May 31. Review. PubMed PMID: 16738015 , Jul-2006
Articles in Peer-reviewed Journals Kisselev AF, Callard A, Goldberg AL. "Importance of the different proteolytic sites of the proteasome and the efficacy of inhibitors varies with the protein substrate." J Biol Chem. 2006 Mar 31;281(13):8582-90. Epub 2006 Feb 2. PMID: 16455650 , Mar-2006
Articles in Peer-reviewed Journals Sacheck JM, Hyatt JP, Raffaello A, Jagoe RT, Roy RR, Edgerton VR, Lecker SH, Goldberg AL. "Rapid disuse and denervation atrophy involve similar transcriptional changes as muscle wasting during systemic diseases." FASEB J. 2007 Jan;21(1):140-55. PubMed PMID: 17116744 [Note originally reported in January 2007 as In press as of January 2006] , Jan-2007
Articles in Peer-reviewed Journals Skurk C, Izumiya Y, Maatz H, Razeghi P, Shiojima I, Sandri M, Sato K, Zeng L, Schiekofer S, Pimentel D, Lecker S, Taegtmeyer H, Goldberg AL, Walsh K. "The FOXO3a transcription factor regulates cardiac myocyte size downstream of AKT signaling." J Biol Chem. 2005 May 27;280(21):20814-23. Epub 2005 Mar 21. PMID: 15781459 , May-2005
Awards Goldberg AL. "Centennial Lecturer, Biochem Society, January 2006." Jan-2006
Awards Goldberg AL. "Elected, American Academy of Arts and Sciences, January 2006." Jan-2006
Download in PDF pdf     
Fiscal Year: FY 2005  Task Last Updated:  06/22/2005 
PI Name: Goldberg, Alfred L Ph.D. 
Project Title: The Activation of Protein Breakdown in Muscle Upon Unloading and Possible Countermeasures 
   
Division Name: Human Research 
Program/Discipline--
Element/Subdiscipline:
NSBRI Teams--Muscle Alterations and Atrophy Team 
 
Joint Agency Name:   TechPort:  No 
Human Research Program Elements: None
Human Research Program Risks: None
Human Research Program Gaps: None
Space Biology Element: None
Space Biology Cross-Element Discipline: None
Space Biology Special Category: None
PI Email: alfred_goldberg@hms.harvard.edu  Fax:  617-232-0173 
PI Organization Type: UNIVERSITY  Phone: 617-432-1855  
Organization Name: Harvard Medical School 
PI Address 1: 240 Longwood Avenue 
PI Address 2: Bldg. C-1, Rm. 415 
PI Web Page:  
City: Boston  State: MA 
Zip Code: 02115-5817  Congressional District: 
Comments:  
Project Type: GROUND  Solicitation:  2003 Biomedical Research & Countermeasures 03-OBPR-04 
Start Date: 03/01/2004  End Date:  02/28/2007 
No. of Post Docs: 10  No. of PhD Degrees: 
No. of PhD Candidates: No. of Master' Degrees: 
No. of Master's Candidates: No. of Bachelor's Degrees: 
No. of Bachelor's Candidates: Monitoring Center:  NSBRI 
Contact Monitor:   Contact Phone:   
Contact Email:  
Flight Program:  
Flight Assignment:

 

Key Personnel Changes/Previous PI:  
COI Name (Institution):  
Grant/Contract No.: NCC 9-58-MA00404 
Performance Goal No.:  
Performance Goal Text:

 

Task Description: The rapid loss of muscle mass that occurs in astronauts in space due to muscle unloading and in patients with many systemic diseases results primarily from accelerated degradation of muscle proteins. This enhancement of protein breakdown is mainly due to activation of the Ub-proteasome pathway. Our major goal is to clarify the biochemical basis for the activation of this proteolytic pathway and thus to develop pharmacological agents that reduce this excessive degradation and retard muscle wasting. Recently, we identified a set of genes ("atrogins") whose expression increases or decreases coordinately when muscles atrophy. In order to achieve a fuller understanding of the atrophy process, we plan to further study this transcriptional program and its regulation, especially after disuse.

Of particular importance was the recent finding that the two genes induced most dramatically in atrophying muscles are the muscle-specific ubiquitin ligases (E3s), atrogin-1 (MAFbx) and MuRF1. If either of these enzymes is knocked out, the extent of muscle wasting is reduced. These Ub-ligases thus are very attractive therapeutic targets. To fully understand the initiation of the atrophy process, and to develop rational countermeasures, we are studying the signal transduction systems that activate transcription of these genes in simple models of muscle atrophy in cultured myotubes. We recently found that the key factor in muscle hypertrophy, IGF-1, rapidly suppresses the expression of atrogin-1 and MuRF1 and prevents their induction by glucocorticoids. These effects of IGF-1 appear to be mediated by the PI3-kinase-AKT pathway, which probably inactivates one of the Forkhead transcription factors. Our primary goals will be to identify the precise steps in this kinase cascade and the key transcription through which disuse and glucocorticoids activate and IGF-1 inhibits expression of atrogin-1 and MuRF1. We shall also examine whether other atrogins are regulated by the same signaling systems and transcription factor.

These studies should identify novel therapeutic targets (e.g. key kinases) whose inhibition blocks atrogin-1 and MuRF1 induction. Using these enzymes and "reporter gene” constructs, we shall screen libraries of small molecules for agents that prevent induction of atrogin-1 and MuRF1. Inhibiting the expression of these key ligases represents an exciting new therapeutic approach to prevent muscle wasting in space personnel and in diverse disease states.

 

Rationale for HRP Directed Research:

 

Research Impact/Earth Benefits: If successful, this research may yield novel therapies to prevent or treat the marked wasting of muscle seen in various bed-ridden patients and ones with systemic disease (cardiac failure, cancer, sepsis, AIDS).

 

Task Progress: See "Main Findings"

 

Bibliography Type: Description: (Last Updated: 09/01/2017) Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Lecker, S. H., R. T. Jagoe, A. Gilbert, M. Gomes, V. Baracos, J. Bailey, S. R. Price, W. E. Mitch, and A. L. Goldberg "Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J" 39-51 , Jan-2004
Articles in Peer-reviewed Journals Sacheck, J. M., A. Ohtsuka, S. C. Mc Lary, and A. L. Goldberg "IGF-1 stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1 Am J Physiol Endocrynol" E591-601 , Apr-2004
Articles in Peer-reviewed Journals Sandri, M., C. Sandri, A. Gilbert, C. Skurk, E. Calabria, A. Picard, K. Walsh, S. Schiaffino, S. H. Lecker, and A. L. Goldberg "Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy Cell" 399-412 , Apr-2004
Awards " 2004 Plenary Lecture of the American Society of Nephrology " Jan-2005
Awards " Annual Fred Fay Lecture (Univ Mass School of Medicine) " Jan-2005
Awards " Dr. Marco Sandri was selected for one of two Telethon Professorships in Italy. He will use it at the University of Padua School of Medicine. " Jan-2005
Awards " One of the 2004 Nobel Lectures (Karolinska Institute, Stockholm, Sweden) " Jan-2005
Awards " Severo Ochoa Lecture (New York University School of Medicine) " Jan-2005
Books/Book Chapters Jagoe, R. T., N. E. Tawa, Jr., and A. L. Goldberg "Protein and amino acid metabolism in muscle Myology" Ed. Engel, A., and C. Franzini-Armstrong McGraw-Hill, 535-564 , Jan-2005
Patents Goldberg, A. L., M. Sandri and S. H. Lecker "Foxo transcription factors are novel pharmacological targets to inhibit skeletal muscle atrophy. " Jan-2005
Presentation Goldberg, A. L. "Functions of the Proteasome in Protein Degradation and Immune Surveillance: From Basic Understanding to Human Therapy " Oct-2004
Presentation Goldberg, A. L. "Induction of Atrophy-Related Genes and the Ubiquitin Ligase, Atrogin-1, in Muscle during Disease States " May-2004
Presentation Goldberg, A. L. "Mechanisms for Induction of the Key Ubiquitin Ligase, Atrogin-1, and Muscle Atrophy in Disease States " Jun-2004
Presentation Goldberg, A. L. "Regulation of the Expression of Atrophy-Specific Ubiquitin-Ligases, Atrogin-1 and MuRF1, in Normal and Atrophying Muscle " Jun-2004
Presentation Jagoe, R. T., J. Sacheck, S. H. Lecker, J. K. Hyatt, A. Gilbert, M. Gomes, V. Baracos, J. Bailey, S. R. Price, W. E. Mitch, R. Roy, V. R. Edgerton, and A. L. Goldberg "Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression " Dec-2004
Presentation Sandri, M., C. Sandri, A. Gilbert, S. Schiaffino, S. Lecker, and A. L. Goldberg "Foxo Transcription Factors Induce the Atrophy-Related Ubiquitin Ligase, Atrogin-1, and Cause Skeletal Muscle Atrophy " Jan-2004
Download in PDF pdf     
Fiscal Year: FY 2004  Task Last Updated:  03/24/2006 
PI Name: Goldberg, Alfred L Ph.D. 
Project Title: The Activation of Protein Breakdown in Muscle upon Unloading and Possible Countermeasures 
   
Division Name: Human Research 
Program/Discipline--
Element/Subdiscipline:
NSBRI Teams--Muscle Alterations and Atrophy Team 
 
Joint Agency Name:   TechPort:  No 
Human Research Program Elements: None
Human Research Program Risks: None
Human Research Program Gaps: None
Space Biology Element: None
Space Biology Cross-Element Discipline: None
Space Biology Special Category: None
PI Email: alfred_goldberg@hms.harvard.edu  Fax:  617-232-0173 
PI Organization Type: UNIVERSITY  Phone: 617-432-1855  
Organization Name: Harvard Medical School 
PI Address 1: 240 Longwood Avenue 
PI Address 2: Bldg. C-1, Rm. 415 
PI Web Page:  
City: Boston  State: MA 
Zip Code: 02115-5817  Congressional District: 
Comments:  
Project Type: GROUND  Solicitation:  2003 Biomedical Research & Countermeasures 03-OBPR-04 
Start Date: 03/01/2004  End Date:  02/28/2007 
No. of Post Docs: No. of PhD Degrees:   
No. of PhD Candidates: No. of Master' Degrees:   
No. of Master's Candidates: No. of Bachelor's Degrees:   
No. of Bachelor's Candidates: Monitoring Center:  NSBRI 
Contact Monitor:   Contact Phone:   
Contact Email:  
Flight Program:  
Flight Assignment:

 

Key Personnel Changes/Previous PI:  
COI Name (Institution):  
Grant/Contract No.: NCC 9-58-MA00404 
Performance Goal No.:  
Performance Goal Text:

 

Task Description: A major problem encountered by space personnel is loss of muscle mass and functional capacity. In addition, muscle atrophy occurs with disuse or neuronal injury and is a debilitating consequence of many systemic diseases including cancer, diabetes, renal failure, and fasting. Our prior work had indicated that the rapid loss of muscle mass in all these conditions is due to excessive breakdown of proteins in the muscle. To establish a comprehensive picture of the changes in gene expression that may be responsible for this acceleration of protein breakdown and muscle wasting, we have used new analytical approaches to analyze muscles of mice with various experimental models of these diseases. By this approach, we have identified and cloned a gene whose expression rises about 10-fold in muscles atrophying due to fasting, cancer, disuse, diabetes, and renal failure. It encodes an enzyme that marks proteins for destruction by linking them to the cofactor ubiquitin. Proteins once linked to ubiquitin are quickly broken down by a particle in all cells called the proteasome. Because atrogin-1 is specifically found in muscles and increases dramatically before the onset of atrophy, we have named it atrogin-1. It appears to be a critical new component in the enhanced protein breakdown that drives muscle wasting in space personnel and in diverse diseases on earth.

 

Rationale for HRP Directed Research:

 

Research Impact/Earth Benefits: Muscle wasting and loss of functional capacity are debilitating consequences of space travel and appear to limit the capacity of astronauts to spend prolonged periods in the absence of gravity. Muscle atrophy on earth is commonly seen with inactivity, fasting, cancer, systemic infections, and other systemic diseases. This loss of muscle protein in all these conditions results primarily from accelerated protein degradation by the ubiquitin-proteasome pathway. The present studies were undertaken to identify key factors that may be important in the acceleration of muscle proteolysis in catabolic states. To establish a comprehensive picture of the transcriptional adaptations that occur during various types of muscle atrophy, and that may be responsible for the activation of protein breakdown, we have used Incyte cDNA microarrays to compare mRNA levels in normal mouse muscles with those from several types of atrophying muscles (manuscript in preparation). Because much is known about the enhancement of proteolysis in muscle and this tissue’s other metabolic adaptations to fasting, we initially performed microarray experiments comparing polyA+RNA from muscles of normal and food-deprived mice, and have identified a group of genes whose transcripts change markedly in the atrophying muscles. As expected, there was a general reduction in the mRNAs for many contractile proteins and for glycolytic enzymes and a 2-3 fold increase in mRNAs for ubiquitin and multiple proteasome subunits, as we had previously found by Northern blot analysis.

One EST was of particular interest because its level increased most dramatically (8-12 fold) upon fasting. Therefore, we have cloned this protein and defined its properties (Gomes, et al, Proc Natl Acad Sci, (2001) 98:25, 14440-14445). We demonstrate here that this protein has the properties of an E3 (ubiquitin protein ligase) of the SCF class, and it is unusual in being expressed selectively in striated muscle. We have also studied further the expression of this gene upon food deprivation, with hind limb suspension, and in several other models of human diseases in which there is a marked acceleration of muscle proteolysis. These studies demonstrate the existence of a novel ubiquitination enzyme that appears to increase whenever muscles undergo atrophy.

This gene is expressed specifically in skeletal muscles and to a much lower degree in heart. Because this mRNA also markedly increases in leg muscles atrophying due to diabetes, cancer and renal failure, as well as disuse (hind-limb suspension) and denervation, we named it atrogin-1. It contains a functional F-box domain that binds to Skp1 and to the other components of SCF-type Ub-protein ligases, Roc1 and Cul1 (E3s). Atrogin also contains a nuclear localization sequence and PDZ-binding domain. Upon fasting, atrogin mRNA levels increase specifically in skeletal muscle and rise before atrophy occurs. Atrogin is one of the few examples of a ubiquitin-protein ligase (E3) expressed in a tissue specific manner, and it appears to be a critical component in the enhanced proteolysis leading to muscle atrophy in diverse diseases. Presumably, atrogin-1 plays a key role in the breakdown of essential growth-related proteins (e.g. regulators of protein synthesis and proteolysis). The major goal of future work will be to clarify its precise role in the atrophy process, to identify its substrates in muscle cells, and to explore ways that atrogin activity may be inhibited.

 

Task Progress: 1) One of the most debilitating responses in space personnel to zero gravity is muscle wasting. Skeletal muscle atrophy is also induced by nerve injury and simple disuse, as well as by fasting and many systemic diseases, including diabetes, cancer, and renal failure (1). Using transcriptional arrays, we have identified a common set of approximately 50 genes (which we termed “atrogenes”) that are strongly induced or suppressed in muscles in these diverse catabolic states (2). Among the strongly induced genes in various metabolic atrophies were many involved in protein degradation, including poly-ubiquitins, the ubiquitin-ligases atrogin-1/MAFbx and MuRF-1, and multiple (but not all) subunits of the 26S proteasome. Among those down-regulated are genes required for ATP production, for extracellular matrix proteins, and for several growth-related mRNAs (P311, JUN) (2).

2) We have described two useful in vitro models of atrophy in cultured muscle cells (with C2C12 myotubes), in which atrophy was induced with the glucocorticoid, dexamethasone, TNFa, or nutrient deprivation (3,4,5). We showed that dexamethasone inhibits growth and enhances the breakdown of myofibrillar proteins, while also increasing atrogin-1 and MuRF1 mRNA (5).

3) By contrast, the growth factors, IGF-1 and insulin prevented these catabolic responses (5). IGF-1 and insulin rapidly reduce atrogin-1 mRNA by blocking its transcription and that of other important atrophy-related genes (atrogenes) (5). IGF-1 and insulin activate the PI3-kinase/Akt pathway, which we showed suppresses proteolysis and atrogin-1 mRNA expression in muscle (5). They also can block the atrophy and atrogene induction by dexamethasone.

4) In the in vitro models of muscle atrophy, glucocorticoid treatment or nutrient deprivation, we also showed that there is a decrease in the PI3K/AKT pathway, activation of the forkhead (Foxo) family of transcription factors, and induction of atrogin-1 (4). Furthermore, IGF-1 by activating AKT causes inhibition of Foxo 1, 2,3 and thus blocks atrogin-1 expression (4).

5) By gene transfection into either myotubes or muscles of adult mice (by electroporation), we showed that Foxo 3, acts directly on the atrogin-1 promoter and causes atrogin-1 expression (4). Also expression of Foxo 3 by itself causes a very dramatic atrophy of cultured myotubes and fibers in adult mouse muscles.

6) Furthermore, when Foxo activation is blocked (by a dominant negative construct or RNAi), the induction of atrogin-1 by glucocorticoids and the resulting reduction in myotube size are prevented (4). Thus, activation of Foxo transcription factor appears to be a key event in the initiation of the atrophy process. On the other hand, inhibition of Foxo function could be a novel approach to combat various forms of muscle wasting (6).

 

Bibliography Type: Description: (Last Updated: 09/01/2017) Show Cumulative Bibliography Listing